It is almost certain now that insulin-dependent (type I) diabetes mellitus is caused by autoimmune processes destroying the insulin producing beta cells. Recent clinical evidence indicates that the autoimmune process may recur after successful pancreas organ transplantation. The overall objective of this proposal is to study pancreatic is)et transplantation in spontaneously diabetic NOD mice, a mouse model for autoimmune diabetes. Three specific aims are proposed. (I) We will establish optimal protocol(s) by which maximal prolongation of islet graft survival is achieved in autoimmune diabetic NOD (nonobese diabetic) mice. Following determination of the minimal number of islets required to restore and maintain normoglycemia in diabetic NOD mice, role of the major histocompatibility complex (MHC) antigens in disease recurrence (MHC restriction) will be analyzed to determine optimal is)et donors. Optimal protocols for in vitro graft modulation and/or recipient treatment will be determined to achieve maximal prolongation of islet allografts. We will examine if treatment of recipients with nondiabetic donor bone marrow and immunosuppression with ALS offers an effective protocol to induce unresponsiveness to alloantigens and resistance to disease recurrence. We will also investigate if multiple donor islet allotransplantation can be successfully applied in NOD mice. (II) We will establish methods by which functional loss by graft rejection and that by disease recurrence could be differentiated. This will be done by simultaneous transplantation of non-islet allografts, by the use of in vitro immunological assays, and by characterization of lymphoid cells infiltrating islets of the NOD mouse and islet allografts. (III) Finally, we will use pancreatic islet transplantation in an attempt to elucidate the mechanism(s) underlying the development of diabetes in NOD mice. We believe that results obtain from these studies will provide important information on the successful application of islet allotransplantation in patients with autoimmune, insulin-dependent diabetes mellitus.